Cervical and vaginal secretions play a protective role in preventing sexually transmitted infections (STI) Defining this activity and identifying the antimicrobial components is crucial as these factors could be exploited in the development of topical microbicides and because vaginal application of drugs should not interfere with critical host defenses. This proposal focuses on the mucosal factors that protect against genital herpes, one of the most prevalent STI and a major co-factor for HIV. Cervicovaginal secretions obtained from healthy women substantially reduce HSV infection and protect mice from vaginal challenge. Preliminary studies suggest that antimicrobial peptides play a key role in this innate protection. The relative contribution and mechanism of anti-HSV activity for human neutrophil peptides1-4, epithelial defensins HD-5 and HD-6, and secretory leukocyte protease inhibitor (SLPI) will be elucidated. HSV must overcome the cervical secretion defenses to establish infection and may have developed strategies to escape these host factors, perhaps through transcriptional regulation. Consistent with this notion, exposure of human cervical epithelial cells to HSV leads to a reduction in SLPI. In addition to serving as an escape mechanism, the changes in the mucosal environment triggered by HSV may enhance susceptibiity to HIV or HIV replication. In additoin to the reduction in SLPI, HSV induces a rapid increase in pro-inflammatory cytokines and chemokines and culture supernatants obtained from HSV-exposed cellss promote activation of latent HIV, mediated in part by IL-6 and TNF-Dlpha. These studies provide a molecular basis for the epidemiological findings of enhanced HIV acquisition in the setting of HSV infection. Building on these observations, the proposed studies will evaluate the interplay between HSV and genital tract mucosal defenses focusing on defensins and SLPI. The paradigm being tested is that genital tract secretions protect against HSV but the virus has developed countermeasures to evade this defense by modulating host protective factors. Moreover, the virus-induced changes may alter the genital tract environment to promote HIV co-infection.